A dual-drug enhanced injectable hydrogel incorporated with neural stem cells for combination therapy in spinal cord injury

Neuronal loss and the formation of glial scars are major pathological events that hinder axonal regrowth and neural regeneration after severe spinal cord injury (SCI). Therapeutic therapies that include both cell transplantation and reducing glial scarring is likely required to achieve substantial functional recovery after severe SCI. In this study, a dual-drug enhanced injectable hydrogel was designed and combined with neural stem cells (NSCs-cfGel) to enhance tissue regeneration in a rat complete transected SCI model. The injectable hydrogel was crosslinked by reversible hydrazone bonds, and the mechanical properties and degradation abilities were analyzed both in vitro and in vivo. When incorporated with two drugs (cetuximab and FTY720), the injectable hydrogel improved both the proliferation and neuronal differentiation and exhibited inhibitory astrocytic differentiation of NSCs in vitro. After transplantation into a rat complete transected SCI model, NSCs-cfGels not only significantly enhanced neuronal differentiation and integration of the grafted NSCs, but also inhibited glial scar formation, and promoted axonal regeneration and nerve circuit reconstruction. Consequently, SCI rats that received NSCs-cfGel implantation exhibited optimal functional improvement. Taken together, this study demonstrates a promising dual-drug enhanced injectable hydrogel for exogenous NSC delivery and thus provides a novel strategy for combination therapy of SCI.